APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia
The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.
Authors
- Daan Moechars (ORCID: https://orcid.org/0000-0002-0079-9778)
- Sriram Balusu (ORCID: https://orcid.org/0000-0003-1424-0577)
- Bart De Strooper (ORCID: https://orcid.org/0000-0001-5455-5819)
- Lutgarde Serneels (ORCID: https://orcid.org/0000-0002-5463-4231)
- Emre Fertan (ORCID: https://orcid.org/0000-0002-0060-5806)
- Leen Wolfs (ORCID: https://orcid.org/0009-0003-5193-6722)
- Renzo Mancuso (ORCID: https://orcid.org/0000-0002-7046-3348)
- Mark Fiers (ORCID: https://orcid.org/0000-0001-5694-2409)
- David A. Klenerman (ORCID: https://orcid.org/0000-0001-7116-6954)
- Disha Shah (ORCID: https://orcid.org/0000-0001-7946-8594)
- Suresh Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Jan Lamote (ORCID: https://orcid.org/0000-0003-1862-958X)
- Pranav Preman (ORCID: https://orcid.org/0000-0002-7282-2615)
- Amaia M. Arranz (ORCID: https://orcid.org/0000-0002-8314-7870)
- An Snellinx
Institutions
- Ikerbasque (ES)
- Allen Institute for Brain Science (US)
- University of Antwerp (BE)
- University of Cambridge (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Achucarro Basque Center for Neuroscience (ES)
- UK Dementia Research Institute (GB)
- VIB-UAntwerp Center for Molecular Neurology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University College London (GB)
- KU Leuven (BE)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2024-11-11
- DOI
- https://doi.org/10.1038/s44321-024-00162-7
- Citations
- 17
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.21
Funders
- Alzheimer's Association
- UK Research and Innovation
- Queen Elisabeth Medical Foundation
- European Commission
- Eusko Jaurlaritza
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaams Instituut voor Biotechnologie
- Ministerio de Ciencia e Innovación
- Vlaamse regering
- UK Dementia Research Institute
- Fondation pour la Recherche sur Alzheimer
- Fondation Médicale Reine Elisabeth
- Medical Research Council
- European Research Council
- Agencia Estatal de Investigación